Determinants of sustained stabilization of beta-cell function following short-term insulin therapy in type 2 diabetes

In early type 2 diabetes, the strategy of “induction” with short-term intensive insulin therapy followed by “maintenance” with metformin can stabilize pancreatic beta-cell function in some patients but not others. We thus sought to elucidate determinants of sustained stabilization of beta-cell function. In this secondary analysis of ClinicalTrials.Gov NCT02192424, adults with ≤5-years diabetes duration were randomized to 3-weeks induction insulin therapy (glargine/lispro) followed by metformin maintenance either with or without intermittent 2-week courses of insulin every 3-months for 2-years. Sustained stabilization (higher beta-cell function at 2-years than at baseline) was achieved in 55 of 99 participants. Independent predictors of sustained stabilization were the change in beta-cell function during induction and changes in hepatic insulin resistance and alanine aminotransferase during maintenance. Thus, initial reversibility of beta-cell dysfunction during induction and subsequent preservation of hepatic insulin sensitivity during maintenance are associated with sustained stabilization of beta-cell function following short-term insulin and metformin. ClinicalTrials.Gov NCT02192424


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of the clinical nature of the data. The study protocol can also be made available in this way. This data access mechanism will be available beginning 9 months and ending 36 months following publication of this article. We will attempt to respond to requests within 3 months, pending Research Ethics Board capacity to do so within this time frame. Source data for figures have been provided with this paper.
Self-reported data on sex were collected and post-hoc exploratory analyses were performed to determine if sex influenced the findings. It should be noted, however, that these were post-hoc analyses, recognizing that the sample size was not designed to be large enough for robust sex-based analyses. Data were not collected on gender, as a potential effect of gender role on the impact of the interventions was not hypothesized a priori.
Self-reported data on ethnicity were collected and post-hoc exploratory analyses were performed to determine if ethnicity influenced the findings. It should be noted, however, that these were post-hoc analyses, recognizing that the sample size was not designed to be large enough for robust ethnicity-based analyses.
Participants were recruited from the practices of family physicians (either by screening charts or physician referral) and in response to advertising of the study. While self-selection can always potentially introduce a bias in clinical trial participation (i.e. since not all people will want to participate in a 2 year trial), it is unlikely to have affected the determinants of sustained stabilization of beta-cell function as reported in this manuscript (i.e. reversible beta-cell dysfunction, hepatic insulin sensitivity). The pre-trial power calculation indicated that a sample size of 88 participants (44 in each arm) would provide 80% power to detect a 20% difference in baseline-adjusted ISSI-2 at 2-years between the MET and MET+IIT arms (based on estimated mean baseline-adjusted ISSI-2 at 2years of 233 and 280, respectively) at significance level (alpha) of 0.05, with standard deviation 100 and assuming a correlation of 0.6 between ISSI-2 at baseline and study end.
Of the 108 study participants, there were 9 individuals whose last study visit occurred at <12-months, representing a duration of follow-up that was considered insufficient for determination of sustained stabilization of beta-cell function. The current analysis was thus performed in the 99 participants in whom sustained stabilization of beta-cell function could be assessed.
A series of sensitivity analyses were performed to confirm robustness of the findings, including analyses in all participants who completed at least 1 study visit after receiving any maintenance therapy (i.e. completed at least the 3-month visit) (n=105). These analyses confirmed the findings reported in the manuscript.
At baseline, participants were randomized to the treatment arms in a 1:1 manner. The Applied Health Research Centre (Toronto) prepared the computer-generated random allocation sequence in variable permuted blocks of sizes 2 and 4, and provided the allocation to the investigators in sealed envelopes that were opened at randomization.
This trial had an open-label design since masking of periodic intensive insulin therapy (IIT) would be impractical. As some protection against bias, the primary outcome of beta-cell function is a physiologic measure that is not readily amenable to manipulation by either participants or providers, and all biochemical analyses were performed by personnel who were unaware of treatment allocation.